Abstract

Regardless of its grounds and hospital treatments the sum of death outcomes caused by cardiovascular reasons is an indicator of survival rate for patients with mild-to-moderate chronic heart failure and is characterized as a combined case. The aim of this study was to investigate influence of metoprolol and atenolol on the combined case in patients with chronic heart failure. The study was comparative, prospective and randomised. The criteria for including in the study were: age of 70 years or less, NYHA functional class II and III, left ventricular ejection fraction ≤40%. One hundred and fifty patients who had been treated by angiotensin converting enzyme inhibitor and by diuretics were divided into three numerically equal therapeutic groups: patients treated by atenolol (”the atenolol group”), patients treated by metoprolol (”the metoprolol group”) and a control group of patients who were not treated by beta blockers. Effects of the treatment were observed for 12 months. The results were analyzed by the SPSS 10.0 statistical software. The cumulative survival rate of patients treated by metoprolol (88%) and by atenolol (78%) was greater than survival rate of patients from the control group (48%). Survival rate of patients treated by metoprolol was also greater then survival rate of patients treated by atenolol. Metoprolol significantly reduced the risk for occurrence of combined cases (71%) compared to atenolol (53%). Results of the study have shown that metoprolol and atenolol have a positive effect on the survival rate of patients with chronic heart failure though metoprolol’s effect is significantly better compared to atenolol.

Key words: chronic heart failure; beta-blockers; metoprolol; atenolol

Introduction

The most important pathophysiological process of chronic heart failure (CHF) is the process of remodeling of the heart ventricles. The remodeling starts and develops primarily due to angiotensins and catecholamines activities [1, 2]. The hypothesis that the medicines that inhibit or reverses the remodeling can prolong CHF patients’ lives got confirmed by the results of large studies on the angiotensin-converting enzyme inhibitors (ACE inhibitors) and beta blockers (β blockers). A long-term use of β blockers has a surprisingly positive effect on overall cardiovascular mortality and morbidity [3-5]. These effects have a solid confirmation only for carvedilol, metoprolol and bisoprolol at mild and moderate CHF, even though according to the professor John G. F. Cleland’s statements, atenolol, propranolol, acebutolol, bisoprolol and betaxolol are used in Europe and US as well [6, 7]. The main question is do different β blockers have a significantly different effect on the CHF patient’s survival rate [7, 8]. Results from the comparative studies (COMET and other) as well as from our study could give the answer on that question in the years that follow [9, 10].

Aim of the work

Aim of the study was to investigate and compare effect of atenolol and metoprolol on the survival rate of patients with CHF of NYHA (New York Heart Association) functional class II and III by observing the combined case as clinical indicator of survival rate. A combined case is defined as the total of death outcomes due to cardiovascular reasons regardless of its grounds and hospital treatments.

Methods

The CHF diagnosis was set based on the guideline of the European Society of Cardiology’s Task Force for Diagnosis and Treatment of Chronic Heart Failure [6]. Echocardiografic examination was performed according to the standardized assessment protocol of American Society of Echocardiography [11]. The criteria for including in the study were: age of 70 years or less, NYHA functional class II and III, left ventricular ejection fraction ≤40%. The criteria for excluding from the study were: systolic blood pressure of 100 mm Hg or less, bradicardia (heart frequency of up to 60 beats per minute) and all degrees of atrioventricular block or sinoatrial node disease, instable angina or myocardial infarct in the last three months, percutan coronar intervention or aortocoronary bypass in the last six months, obstructive or restrictive cardiomyopathies, congenital heart disorder, primary valvular disease or artificial valves, terminal diseases of other systems or organs, all known contraindications to beta-blockers application and the information about current treatment by β blockers. Patients were divided into three numerically equal therapeutic groups: patients treated by ACE inhibitor and diuretic – the control group (50 patients), patients treated by atenolol, ACE inhibitor and diuretic – the atenolol group (50 patients) and patients treated by metoprolol, ACE inhibitor and diuretic – the metoprolol group (50 patients).

The study was comparative, prospective and randomised. β blockers application start was determined by the phase when a patient was clinically ”dry” for two weeks. The initial atenolol dose was 25 mg once daily and initial dose of metoprolol tartrate was 25 mg divided in two daily doses. Farther titrational scheme was individual; target dose for both atenolol and metoprolol was 100 mg daily. The therapeutic effect has been followed for 12 months. The control examinations were performed after 1, 3, 6 and 12 months from start of the treatment. The study has been ongoing for 39 months. At each control we followed: possible negative effects of the β blockers treatment (symptomatic aggravation of CHF, symptomatic hypotension, symptomatic bradycardie), new cardiovascular diseases and new additional diseases independent of the cardiovascular system, bad compliance, death of a patient regardless of the cause. During the study we excluded from examinations all patients who had permanently discontinued intake of β blockers due to bad compliance or due to new additional disease independent of the cardiovascular system.

The statistical analyses were performed in the SPSS 10.0 program package and they comprised: X2-test, analysis of variance for investigation of differences in demographic characteristics and frequency of unfavorable events, Kaplan-Meier survival model curve for distribution of combined cases as function of time, equality test performed by log-rank statistics, Wilcoxon statistics for the determination of survival rate between two patients groups, Cox regression model FW (Forward Wald) for examination of relative risk for occurrence of combined case in the three groups of patients. In the beginning of study there were no significant differences in age, gender, systolic blood pressure and heart frequency, etiology CHF, NYHA class, ejection fraction, i.e. other diseases as hypertension and diabetes, between the CHF patients from three therapeutic groups (Table 1).

Results

The differences in deaths rates between the examined CHF patients groups were not statistically significant (Table 2). A statistical significant difference among the patients from the three therapeutic groups was found in the number (frequency) of hospitalisations due to cardiovascular diseases and in the number (frequency) of the combined cases. Frequency of hospitalisation in the metoprolol group (4%) was significantly less compared to the atenolol group (12%) and compared to the control group (26.3%). Combined case frequency in the metoprolol group (8%) was significantly less compared to the atenolol group (16%) and compared to the control group (26.3%) (Table 2). Kaplan-Meier’s survival rate curves were significantly different for different therapeutic groups of patients (log-rank 16.46; df=2; p=0.0003) as shown in the Graph 1. In the end of investigation the cumulative survival rate in the metoprolol group was 0.88 (88%), in the atenolol group 0.78 (78%) and in the control group 0.48 (48%). The survival rate of patients treated by atenolol was significantly greater compared to control group while the survival rate of patients treated by metoprolol was significantly greater compared to the control group as well compared to patients treated by atenolol (Table 3). It was determined that metoprolol significantly reduces the relative risk for emerging of combined cases (71.3%; ExpB 0.287; p=0.020) compared to atenolol (53.4%; ExpB 0.466; p=0.050). In the end of the study average daily doses of atenolol were 50±12.25 mg and average daily doses of metoprolol were 65.50±20 mg.

Discussion

Results of our study are further confirmation of the β1 selective antagonists’ favorable effect on development and outcome of chronic heart failure. The ground for this favorable effect lies in the deformations of adrenergic signaling in insufficient myocardium [1, 12]. A long and intensified stimulation by catecholamines leads to devastating biological effects on the myocytes level due to stimulation of β adrenergic receptors. These effects cause remodeling signals and evolution of malignant arrhythmia [12, 13]. As the ratio of β1 receptors and β2 receptors in the heart ventricles is 80:20% and due to the fact that noradrenalin performs its effects mainly through the β1 receptors, the adaptation of myocytes against the exaggerated stimulation happens foremost by reducing the number and sensitivity of β1 receptors. Another adaptive response of the myocytes is stimulation of iRNA and β adrenoceptor kinase (β-ARK) activities, as well as stimulation of activity of inhibitory subunit guanin-protein (Gi), what causes phosphorylisation of β receptors and prevents connecting to agonist (so called, functional uncoupling). These transformations in β adrenergic signaling explicitly disturb ability of the heart to increase its contractility to meet the hemodynamic needs. Application of the β1 blockers establishes a beneficial balance in so called cross-talk of the β1 and β2 receptor molecules, as proved in many studies [12-16]. The primary aims of the large studies as the total or cardiovascular mortality, cardiovascular morbidity or hospitalisation due to CHF progression and combined cases, have proved as acceptable clinical indicators of survival rate. More than 90% of the patients who were treated by β blockers, from the studies performed so far, had been previously treated by ACE inhibitor and diuretic [17, 18]. Reports from all finished studies confirm that β blockers significantly reduce mortality and morbidity. Results of our study are just another contribution to the previous studies. The most recent meta-analysis of the β blockers in CHF, published in 2000, includes 22 randomised, placebo-controlled studies, comprising more than 10,000 patients. The authors have concluded that treatment by β blockers reduces occurrence of combined case (the total mortality and hospitalisation due to CHF) by almost a 100% among the patients of NYHA class II and III. What practically means 3.8 saved lives out of 100 treated patients. At the same time β blockers reduce number of hospitalisations by four out of a 100 treated patients [1, 19]. The main question is do different β blockers have a significantly different effect on the CHF patient’s survival rate.

Results from the biggest comparative study (COMET) as well as the other smaller studies show that carvedilol has a more favorable effect on the survival rate than metoprolol. Number of death outcomes by all causes in the COMET study was significantly lower among the carvedilol patients group (34%) compared to the metoprolol group (40%), but numbers of the combined cases (death and hospital treatments regardless of its grounds) were not significantly different between patients treated by carvedilol (74%) and metoprolol (76%) [9]. The assumption that carvedilol’s ”advantage” over metoprolol lies ”outside” β1 blockade was disturbed by the observation that extent of β1 blockade by metoprolol (tartrate formulation, average daily dose 85 mg) in the COMET study was significantly lower than in the previous studies in which patients were treated by metoprolol. This observation impels carefulness while estimating some β blockers’ ”advantage” and opens a question about dosage and formulation of the medicine in other comparative studies, regardless of applied β blocker [20].

In our study we compared the effects of metoprolol-tartrate, a β1 blocker, with another β1 blocker – atenolol. This way we observed the effects of adrenoreceptor antagonists on combined case only within the β1 blockade. The both β1 blockers showed positive effect on the clinical development and outcome of CHF among the patients from the control group. While the effect of metoprolol (tartrate formulation, average daily dose 65.50±20 mg) was significantly better compared to atenolol’s effect (average daily dose 50±12.25 mg). It is possible that reasons for the variance could be connected to the different moduling of β adrenergic signaling. Namely, metoprolol has dominant β1 receptor activity and proved ability to recover the number and sensitivity of β1 adrenoreceptors [12]. Regardless of the negative inotropic effect, metoprolol in some way makes the β2 receptors sensible, redirects adrenergic signaling towards the β2 receptors, normalises the β-ARK and Gi activity and puts into balance the receptorial stimulation and inhibition of myocytes [1, 12, 21, 22]. Atenolol normalises β1 adrenergic signaling as well. But the β1 and β2 receptorial activities ratio is much greater. The expected result of such receptorial activity could be symptomatic bradycardia or symptomatic deterioration of CHF i.e. reduced drug tolerance. Which mechanisms initiate the favorable and which initiate the unfavorable occurrences during the β1 blockade is not clear yet [1, 21, 22]. Metoprolol tartrate, unlike atenolol, is liposoluble i.e. can easily pass emato-encefalic barrier. It has been proved that its primarily effect can prevent occurrence of lethal arrhythmia [23]. All the stated influences that metoprolol has on adrenergic signaling can – to some extend – explain the better tolerance and more favorable effects of metoprolol on the survival rate of patients with mild-to-moderate CHF, compared to atenolol, even though the molecular mechanisms that lie as a ground for the different effects of these β blockers of the same generation, are for the time being not sufficiently investigated.

Conclusion

In patients with chronic heart failure NYHA functional class II and III of different etiologies, previously treated by ACE inhibitors and diuretics, both of the β1 blockers (metoprolol-tartrate and atenolol) reduce the total mortality and cardiovascular morbidity compared to the control group of patients, while the metoprolol’s effect on the survival rate is significantly better and the application safer compared to the effect and application of atenolol.

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